Abstract
Purinergic signalling plays an important role in the regulation of bladder smooth muscle (BSM) contractility, and P2X4 receptor is expressed in the bladder wall, where it may act by forming heteromeric receptors with P2X1, the major purinergic force-generating muscle receptor. To test this hypothesis, we examined mouse BSM contractile properties in the absence and presence of selective P2X1 (NF449 & NF279) and P2X4 antagonists (5-BDBD). These drugs inhibited BSM purinergic contraction only partially, suggesting the possibility of a heteromeric receptor. However, carefully controlled co-immunoprecipitation experiments indicated that P2X1 and P2X4 do not form physically linked heteromers. Furthermore, immunofluorescence staining showed that P2X4 is not present in mouse BSM per se, but in an unknown cellular structure among BSM bundles. To investigate whether deletion of P2X4 could impact voiding function in vivo, P2X4 null mice were characterized. P2X4 null mice had normal bladder weight and morphology, normal voiding spot size and number by voiding spot assay, normal voiding interval, pressure and compliance by cystometrogram, and normal BSM contractility by myography. In conclusion, these data strongly suggest that P2X4 is not present in mouse BSM cells, does not affect smooth muscle contractility and that mice null for P2X4 exhibit normal voiding function.
Highlights
The prevalence of lower urinary tract symptoms (LUTS) is extremely high, affecting ~50% of the population aged more than 40 years old[1,2], and the major symptoms of LUTS are manifested by bladder contraction and relaxation disorders
During electric field stimulation (EFS), bladder smooth muscle (BSM) contraction is stimulated through cholinergic and non-cholinergic neurotransmitter release
We showed that it was able to inhibit EFS induced atropine-resistant BSM contractions at concentrations between 0.5–50 μM (Fig. 1D), indicating that P2X4 might be involved in BSM contraction
Summary
The prevalence of lower urinary tract symptoms (LUTS) is extremely high, affecting ~50% of the population aged more than 40 years old[1,2], and the major symptoms of LUTS are manifested by bladder contraction (voiding) and relaxation (storage) disorders. Externally applied α,β-meATP (as opposed to EFS-stimulated neuronal release) elicited significant human BSM contraction, and purinegic receptors like P2X1 is highly expressed in human bladder[5,6]. In diabetic rat models like streptozotocin (STZ) treatment or Zucker obese rats, bladders exhibited significant non-cholinergic and non-α,β-meATP sensitive contractions accounting for 20% of total nerve mediated contractile force[20,21]. These results suggest that there are additional P2 receptors active in BSM and abundant expression of P2X4 has been observed by immunostaining in BSM as well as in other smooth muscle[22]. We have determined the role of P2X4 in overall voiding function by studying a P2X4 knockout mouse
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